HIV-1 protease inhibitors (PI)-based Highly Active Antiretroviral Therapy (HAART) has increased life expectancy in the HIV-infected. Recently, there has been increasing concern over reports of abnormal glucose and lipid metabolism, endothelial dysfunction, as well as even reports of cardiac events in HIV-infected patients receiving PI-based HAART. With increasing longevity in this population that uses PIs for lifelong treatment, this portends ominous increases in morbidity, mortality and health care costs from therapy-based complications such as diabetes and coronary disease. However, some of these complications have been reported in untreated patients, as well as in those on PI-free HAART. Thus, it remains to be defined if the heightened vascular risk is due to PI alone, HIV infection alone, or an interaction between the two. Recent preliminary data from our laboratory suggest that in HIV-negative non-obese subjects, the PI indinavir (IDV) induces endothelial dysfunction as well as insulin resistance (IR). We propose to dissect out the sites of IDV-induced IR, the role of IDV in the induction of endothelial dysfunction in the absence of infection, IR as the mechanism underlying IDV-induced endothelial dysfunction, and the role of adipocyte dysfunction in the above metabolic and vascular changes, and its prevention. We will study insulin sensitivity, beta cell function, endothelial function, lipid parameters, newly recognized vascular risk factors as well as adipocyte differentiation in healthy HIV-negative non-obese subjects before and after 4 weeks of IDV/placebo, and the effect of prevention of impaired adipocyte function on the above parameters before and after 4 weeks of co-administration of IDV and the thiazolidinedione, rosiglitazone in a similar group of subjects. We will test the following hypotheses: 1) IDV induces IR at the level of muscle, fat and liver, and impairs beta cell function. 2) IDV induces endothelial dysfunction, partly through induction of IR. 3) IDV induces changes in IR-related qualitative lipid parameters and non-traditional vascular risk factors, thus supporting IR as the basis for the endothelial dysfunction. 4) Rosiglitazone will prevent IDV-induced adipocyte changes, and thus IR as well as endothelial dysfunction. Thus, results from our studies will help define IDV-associated vascular risk, the underlying mechanism, and a possible means of preventing the same.